Abstract Periodontal diseases affect 42% of adult Americans and are characterized by bacterial-driven inflammatory bone loss. Traditional and emerging treatments for periodontitis management do not typically target the host immune response, which is the major source of tissue damage. The demethylation activity of the chromatin remodeling enzyme lysine-specific demethylase 1 (KDM1A) at the transcription activating mark histone 3 lysine 4 (H3K4) leads to a decrease in pro-inflammatory cytokine transcription. By contrast, the chromatin remodeling enzyme lysine specific demethylase 4B (KDM4B) specifically demethylates the transcription deactivating mark histone 3 trimethyllysine 9 (H3K9me3), leading to up regulated expression of pro-inflammatory cytokines (PICs). Interestingly, cross talk between these two enzymes leads to a balanced system wherein lysine 9 hypomethylation by KDM4B serves as a prerequisite to lysine 4 hypomethylation by KDM1A. The research plan outlined in this proposal will exploit this crosstalk for the design of new chemical probes for use in the study of the epigenetic basis for PD. The the central hypothesis of this study is that promotion of KDM1A activity by introduction of a specific KDM4B or KDM4E inhibitor will alleviate PD by reducing the expression of PICs in diseased tissue and reducing osteoclast formation. Inhibitors so identified will be useful as chemical probes to study the biochemical basis of inflammation and bone loss in PD. We will test this hypothesis through completion of the following Specific Aims: Specific Aim 1: We will use structure-based design techniques to discover novel inhibitors of KDM4B or 4E for use as chemical tools to elucidate the mechanism underlying inflammation and bone loss in PD; Specific Aim 2: We will define the cellular mechanism by which KDM4B/4E over expression contributes to periodontal inflammation and bone loss; Specific Aim 3: We will evaluate novel and known KDM4B/4E inhibitors for immunomodulatory activity in vivo using two models of PD. Our preliminary results demonstrate that KDM4B and 4E protein is more abundant in vivo in periodontally diseased connective tissue, and that inhibition of KDM4B results in significant decreases in PIC production and osteoclastogenesis in tissue pre-treated with a periopathogenic lipopolysaccharide. New and existing inhibitors will be used to further validate KDM4B as a therapeutic target in PD, and computational chemistry docking experiments paired with physical compound screens will be employed to correlate compound structure and changes in disease progression markers. Selected KDM4B inhibitors will be interrogated both in vitro and in vivo for efficacy and toxicity. This study will provide a more robust understanding of epigenetic mechanisms that play a significant role periodontal disease progression, validate KDM4B as a drug target for periodontitis, and result in development of chemical probes with therapeutic potential for local immunomodulatory adjuvant treatment of PD. This project will break down barriers between the fields of periodontics and drug design and will foster the development of knowledge on a critically needed aspect of translational oral health science.